Melphalan, (4-[bis(2-chloroethyl)amino]-L-phenylalanine), is a nitrogen mustard that is useful as a chemotherapeutic agent against many tumors. With cells grown in culture, it is effective against many brain tumors. However, it is poorly transported across the blood brain barrier and thus has not been found effective for use against many brain (intracranial) tumors.
It has been discovered that starving followed by a protein-free diet reduces plasma levels of protein amino acids including large neutral amino acids and increases the blood-to-tumor periphery tissue transfer constant of melphalan both for subcutaneous tumors (representative of all tumors except for brain tumors) and also for brain tumors. See Friedman, H. S., et al, Proceedings of the American Association for Cancer Research, Volume 32, page 318, Abstract 1886, March, 1991. This increase of blood-to-tumor tissue transfer constant might be expected to allow use of lesser dosages of melphalan (and concomitant reduced toxicity) in circumstances where melphalan is now considered useful and the extension of use of melphalan in circumstances now foreclosed by the blood brain barrier, i.e., as an anti-tumor agent against brain (intracranial) tumors. However, the accomplishment of this by means of starving and administration of a protein free diet affords at most limited improvement.
The finding that reduced plasma levels of large neutral amino acids were associated with increased blood-to-tumor melphalan transfer constants is consistent with previous work showing that melphalan is transported by the same transporter as the large neutral amino acids and that the presence of large neutral amino acids in plasma interferes with the transport of melphalan. Thus achieving reduction of plasma levels of large neutral amino acids by means different from or additional to restricted diet to the same or greater degree as is obtained with said restricted diet, should improve melphalan transport and result in a benefit if said different means doesn't concurrently provide deleterious effect.
Various enzymes are known for which large neutral protein amino acids are substrates and which would be useful for reducing plasma levels of these provided they have access to required cosubstrates. However, melphalan is also an amino acid and would likely be a substrate for the same enzymes. Furthermore, the various possible enzymes would be expected to differ in respect to the number of different large neutral amino acids that would be substrates and in their relative kinetic constants vis-a-vis their large neutral amino acid substrates and melphalan. Therefore, such enzymes might be expected, on the one hand, to potentiate the transport of melphalan into tumors by reducing concentrations of plasma large neutral amino acids but on the other hand, would be expected to act in counterproductive fashion by degrading melphalan to an extent which might be larger than the extent of increased melphalan transport from large neural amino acid depletion. Furthermore, each particular enzyme might be expected to have different effects on concentrations of plasma large neutral amino acids and the degradation of melphalan. What is necessary is selection of an enzyme which will reduce plasma large neutral amino acids to enhance melphalan transport but which would be relatively less active toward melphalan or which would be sufficiently inactivated, within the period of reduced plasma amino acid level, so as not to degrade the melphalan to an extent of negating the benefit obtained by enhanced melphalan transport. For any particular enzyme, there is no expectation of success of meeting this criterion.